Methods Of Improving The Pharmacokinetics Of Doxepin

ABSTRACT

Methods of improving the pharmacokinetics of doxepin in a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/007,334, filed Jan. 14, 2011, which is a continuation of U.S.application Ser. No. 11/781,165, filed Jul. 20, 2007, which claimspriority to U.S. Provisional Application Nos. 60/832,727 and 60/833,617,respectively filed on Jul. 20, 2006 and Jul. 24, 2006, both entitledMETHODS OF IMPROVING THE PHARMACOKINETICS OF DOXEPIN. The disclosure ofeach of the above-described applications is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods of improving thepharmacokinetics of doxepin in a patient.

BACKGROUND OF THE INVENTION

The term “food effect” refers to a somewhat unpredictable phenomenonthat can influence the absorption of drugs from the gastrointestinaltract following oral administration. A food effect can be designated“negative” when absorption is decreased, or “positive” when absorptionis increased and manifested as an increase in oral bioavailability (asreflected by total exposure, usually defined as AUC). Alternatively,food effects can refer to changes in maximum concentration (C_(max)), orthe time to reach maximum concentration (T_(max)), independently ofoverall absorption. As a result, some drugs have to be taken in eitherfasted or fed conditions to achieve the optimum effect. For example,patients may be instructed to take a drug with a meal, before a meal(e.g., one hour before a meal), or after a meal (e.g., two hours after ameal). However, many drugs are unaffected by food, and thus, can betaken in either a fasted or a fed condition.

Doxepin is a tricyclic compound currently approved for treatment ofdepression and anxiety. The recommended daily oral dose for thetreatment of depression or anxiety ranges from 75 milligrams to 300milligrams. Also, U.S. Pat. Nos. 5,502,047 and 6,211,229 describe theuse of doxepin for the treatment chronic and non-chronic (e.g.,transient/short term) insomnia. Doxepin, unlike most FDA-approvedproducts for the treatment of insomnia, is not a Schedule IV controlledsubstance. Historically, doxepin pharmacokinetics have not been known tobe affected by food.

In treating depression, anxiety and sleep disorders it is beneficial tooptimize the pharmacokinetics of the administered medication in apatient. For example, in the case of sleep disorders a patient may havea set window of time within which they desire that their sleep occur.Thus, it can be useful to minimize the amount of time required to attaina maximum concentration of a drug in order to receive the therapeuticbenefit of the drug as soon as possible during the desired treatmentperiod.

SUMMARY OF THE INVENTION

Some embodiments are based upon the surprising discovery about the foodeffects of doxepin. For example, as described more fully below, it hasbeen discovered that administration of doxepin without food decreasesthe time to achieve maximum blood concentration or T_(max) for doxepin.In one experiment, the administration of doxepin without food resultedin achieving T_(max) three hours more quickly than when doxepin wasadministered with food. As another example, it has been discovered thatadministration of doxepin with food increases the overallbioavailability of doxepin and results in a higher maximum concentration(C_(max)) of doxepin. In one experiment, the administration of doxepinwith food resulted in a 41% increase in bioavailability (AUC_(0-∞)) anda 15% increase in C_(max) compared to administration in a fasted state.

As a result of the various discoveries related to the food effects ofdoxepin and depending upon the type of therapy and the desired overallresult of that therapy, a patient can benefit from a number of differenttherapeutic regimens. Disclosed are various therapeutic regimensinfluenced by the food effects observed with doxepin.

Achieving a More Rapid Maximum Concentration (T_(max))

In some circumstances, more rapid onset of doxepin action may bedesired. One embodiment relates to a method of shortening the timerequired to achieve a maximum plasma concentration of doxepin in apatient receiving doxepin therapy, which method can includeadministering to the patient a therapeutically effective amount ofdoxepin in a pharmaceutical composition without food. The methods canhave various benefits, including more rapid onset of drug action,shorter duration of effect, etc. The administration to the patient canoccur, for example, at least about 30 minutes, at least about 1 hour, atleast about 2 hours, at least about 3 hours or at least about 4 hours,or more after consuming food. Also, administration to the patient canoccur at least about 30 minutes, at least about 1 hour, at least about 2hours, at least about 3 hours, or at least about 4 hours, or more priorto consuming food, for example.

Sleep Therapy:

Another embodiment relates to methods of treating sleep disorders. Adesirable sleep medication preferably can have the ability to affect theonset of drug action and the duration of drug activity (e.g., to avoidhangover, etc.). Generally, a person will desire to fall asleep as soonas possible, to stay asleep for about 8 hours, and to wake up withouthangover or extra sedation at the end of the 8 hours. As mentionedabove, surprisingly, the administration of doxepin without food resultedin achieving a maximum concentration of the drug three hours soonercompared to administration with food. As a result, when treating sleep,doxepin can be taken without food in order to achieve earlier onset ofdrug action and/or a shorter duration of drug action.

Thus, some embodiments relate to a method of shortening the timerequired to achieve sleep onset, which method can include administeringto the patient a therapeutically effective amount of doxepin in apharmaceutical composition without food. Also, another embodimentrelates to a method of treating a sleep disorder comprising providing apatient with a therapeutically effective amount of doxepin and providingthe patient with instructions to take the doxepin without food. Thedoxepin can be provided to the patient at least about 30 minutes, atleast about 1 hour, at least about 2 hours, at least about 3 hours or atleast about 4 hours or more after consuming food, or at least about 30minutes, or at least about 1 hour prior to consuming food.

Still a further embodiment relates to a method of treating a sleepdisorder comprising providing a patient with a therapeutically effectiveamount of doxepin and providing the patient with information regarding adoxepin food effect. The information can be provided orally or inwritten form. Some exemplary written forms include a label associatedwith the drug, on the container for the drug, packaged with the drug, orseparately given to the patient apart from the drug.

Still some embodiments relate to the use of doxepin in the preparationof a medicament for treatment of a sleep disorder, said medicament foradministration without food. Also, the use can further be for shorteningthe time required to achieve a maximal plasma concentration of doxepinby administration without food. The administration without food canoccur when the patient is in a fasted state. The administration withoutfood can occur, for example, at least about 30 minutes, at least about 1hour, at least about 2 hours, at least about 3 hours or at least about 4hours, or more after consuming food. Also, it can occur, for example, atleast about 30 minutes, at least about 1 hour, at least about 2 hours,at least about 3 hours, or at least about 4 hours, or more prior toconsuming food. In some aspects, the administration of the doxepin canoccur, for example, at least about 30 minutes, at least about 1 hour, ormore prior to consuming food.

Achieving a Greater C_(max) or a Greater Bioavailability GreaterC_(max):

Some embodiments relate to a method of increasing the maximum plasmaconcentration of doxepin in a patient receiving doxepin therapycomprising administering to the patient a therapeutically effectiveamount of doxepin in a pharmaceutical composition with food.

Greater Bioavailability:

Also, some embodiments relate to methods of increasing the oralbioavailability of doxepin, including by administering to a patient anamount of a pharmaceutical oral dosage form of doxepin with food.Further embodiments relate to methods of increasing the oralbioavailability of doxepin to a patient receiving doxepin therapy, whichmethods can include administering to the patient an amount of apharmaceutical oral dosage form of doxepin with food, wherein theadministration results in an AUC_(0-∞) that is greater than thatachieved by the administration of the same amount of doxepin withoutfood. In such methods, the doxepin can be administered as part of achronic doxepin therapy, for example.

Anxiety/Depression Therapy:

Still another embodiment relates to methods of treating depression oranxiety. It is worth noting that improved pharmacokinetics of doxepin inthe context of depression or anxiety can be beneficial, for example by,leading to more safe and effective dosing. The methods of treatingdepression or anxiety can include administering a therapeuticallyeffective amount of doxepin preferably with food. In some embodimentsthe depression or anxiety can be treated by administering doxepinwithout food. Also, some embodiments relate to methods of treatingdepression or anxiety, including by providing a patient with atherapeutically effective amount of doxepin and providing the patientwith instructions to preferably take the doxepin with food. In somealternative embodiments, the instructions can specify taking the doxepinwithout food.

Another embodiment relates to a method of treating depression or anxietycomprising providing a patient with a therapeutically effective amountof doxepin and providing the patient with information regarding adoxepin food effect.

Also, some embodiments relate to the use of doxepin in the preparationof a medicament for treatment of a psychological disorder, saidmedicament for administration with food. The disorder can preferably bedepression or anxiety. The use also can be for the preparation of amedicament for increasing the oral bioavailability of doxepin byadministration with food; for increasing the oral bioavailability ofdoxepin to a patient receiving doxepin therapy by administering anamount of a pharmaceutical oral dosage form of doxepin with food,wherein the administration results in an AUC_(0-∞) that is greater thanthat achieved by the administration of the same amount of doxepinwithout food; for increasing the time required to achieve a maximalplasma concentration of doxepin by administration with food; forminimizing side effects associated with a doxepin treatment of thepsychological disorder, by administering a therapeutically effectiveamount of doxepin with food, which can result in the patient receivingor in a physician prescribing a lower dosage of doxepin compared thedosage that is taken by the patient without food; or for improving theconsistency of pharmacokinetics associated with doxepin therapy, inwhich a patient receives a multiple doxepin dosages over multiple days,comprising administering the doxepin in a fixed temporal relationship tofood intake by the patient.

Decreasing Bioavailability:

It should be noted that some embodiments relate to methods of decreasingthe oral bioavailability of doxepin. Decreasing oral bioavailability canbe beneficial in some contexts. For example, as mentioned above forsleep therapies, it can be beneficial to shorten the duration of thedrug action in order to minimize hangover or other effects. The methodsof decreasing bioavailability can include administering to a patient anamount of a pharmaceutical oral dosage form of doxepin without food.Furthermore, some embodiments relate to methods of decreasing the oralbioavailability of doxepin to a patient receiving doxepin therapy,comprising administering to the patient an amount of a pharmaceuticaloral dosage form of doxepin without food, wherein the administrationresults in an AUC_(0-∞) that is less than that achieved by theadministration of the same amount of doxepin with food. In such methods,doxepin can be administered as part of a chronic doxepin therapy, forexample. Also, in such methods administration to the patient can occur,for example, at least about 30 minutes, at least about 1 hour, at leastabout 2 hours, at least about 3 hours or at least about 4 hours, or moreafter consuming food. Also, administration to the patient can occur atleast about 30 minutes, at least about 1 hour, at least about 2 hours,at least about 3 hours, or at least about 4 hours, or more prior toconsuming food, for example.

Minimizing Doxepin Side Effects and Improving PharmacokineticConsistency

Some embodiments relate to methods of minimizing side effects associatedwith a doxepin therapy. The methods can include, for example,administering a therapeutically effective amount of doxepin to a patientwith food. Also, the administration of doxepin with food can result in apatient receiving or a physician prescribing a lower dose of doxepincompared to the dosage prescribed without food.

This disclosure includes a method for improving the consistency ofpharmacokinetics associated with doxepin therapy, in which a patientreceives multiple doxepin dosages over multiple days, comprisingadministering the doxepin to the patient in a fixed temporalrelationship to food intake by the patient. This can, for example,include providing written or verbal instructions to the patient to takethe doxepin in a fixed temporal relationship to food intake by thepatient. Taking doxepin in a fixed relationship to food can help assuremore consistent efficacy of the medication.

Other Food Effect Methods

Also, some embodiments relate to methods of alleviating a doxepin foodeffect or altering a doxepin pharmacokinetic parameter in a patient, forexample, by administering doxepin to a patient in need thereof, whereinthe patient is in a non-fasted state or in a fasted state.

Further embodiments relate to a method of treating a disorder withdoxepin comprising providing a patient with a therapeutically effectiveamount of doxepin and providing the patient with information regarding adoxepin food effect. The information can include, for example,instructions to take the doxepin with or without food, or to ensure thatdoxepin is consistently taken either with or without food. Theinformation can be in an oral or written form. Some exemplary writtenforms include a label associated with the drug, on the container for thedrug, packaged with the drug, separately given to the patient apart fromthe drug, or provided in manner that the patient can independentlyobtain the information (e.g., a web site).

Dosage and Compositions

Again, in the various disclosed embodiments, the amount of doxepin,including the therapeutically effective amount, may advantageously be,for example, about 0.001 milligram to about 350 milligrams, preferablyabout 50 milligrams to about 300 milligrams or more preferably about 75milligrams to about 300 milligrams, or any amount or sub-range withinthose ranges. Alternatively, the effective amount may be about 0.5milligrams to about 20 milligrams, more preferably about 1 milligram toabout 6 milligrams.

Also, in the various disclosed embodiments, the pharmaceuticalcomposition of doxepin can be, for example, a tablet, capsule or liquid.Furthermore, the doxepin can be provided or administered as a unitdosage form. Preferably, the doxepin can be provided or administered asan oral dosage form.

Doxepin Kits and Products

Finally, the present disclosure also includes a kit or a product thatincludes doxepin and written instructions or information associatedtherewith to take the doxepin without food. For example, theinstructions can specify that doxepin be administered to the patient atleast about 30 minutes, at least about 1 hour, at least about 2 hours,at least about 3 hours, at least about 4 hours or more after consumingfood, or at least about 30 minutes, at least about 1 hour, at leastabout 2 hours, at least about 3 hours, at least about 4 hours or moreprior to consuming food, for example. In some aspects, the kits orproduct can include instructions that describe administration to thepatient preferably at least about 30 minutes or at least about 1 hourprior to consuming food. The kit or product can include informationregarding a food effect associated with doxepin. Alternatively, itincludes a kit or a product comprising doxepin and written instructionsassociated therewith to take the doxepin with food.

The product or kit can include doxepin in amount of about 0.5 milligramto about 350 milligrams, preferably about 50 milligrams to about 300milligrams or more preferably about 75 milligrams to about 300milligrams. Alternatively, the amount may be about 0.5 milligrams toabout 20 milligrams, more preferably about 1 milligram to about 6milligrams. Some preferred amounts are about 1 milligram, about 3milligrams and about 6 milligrams.

Finally, the product or kit can include doxepin as a tablet, a capsule,a liquid, a unite dosage form or an oral dosage form, for example.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the design of a study of food effect associated withdoxepin.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments described herein relate to the novel and unexpecteddiscovery of a food effect associated with doxepin. As described morefully below, a single-center, phase 1, randomized, open-label, singledose, two-way crossover study was conducted in 16 healthy young adultmale and female volunteers. A food effect was observed on thepharmacokinetics of doxepin. In the fed state, pharmacokineticparameters (AUC_(0-∞) and C_(max)) of doxepin were approximately 41% and15% higher, respectively, compared to the fasted state, and medianT_(max) was delayed by approximately 3.0 hours in the fed state. Theincrease in AUC was statistically significant and demonstrates apositive food effect on exposure. The increased T_(max) in the fed statesuggests that food slows the absorption of the drug.

Accordingly, some embodiments relate to methods of improving thepharmacokinetics of doxepin in a patient. As discussed above and morefully elsewhere herein, administration of doxepin in a fasted state canresult in decreasing the time required to achieve a maximum plasmaconcentration of doxepin. In particular, the time to reach maximumconcentration (T_(max)) of doxepin can be minimized by administering thedrug without food. Also, as discussed above and more fully elsewhereherein, administration of doxepin with food can increase the overallbioavailability of the drug. For example, the time to reach maximumconcentration can be increased by administering doxepin with food andthe bioavailability of the drug can be increased.

In addition, in a different embodiment, the total effective amount ofdrug that the patient receives can be maximized by administering doxepinwith food, while in other embodiments the oral bioavailability ofdoxepin can be decreased by administering the doxepin without food.Because plasma concentrations and half-lives of doxepin are alreadyknown to vary from patient to patient, knowledge of the doxepin foodeffect can help patients and physicians to eliminate this additionalsource of dosing uncertainty, to improve safety and tolerability, andimprove therapies that utilize doxepin. For example, as described morefully elsewhere herein, depending on the effect desired, doxepin can betaken with food; it can be taken after the patient has gone without foodfor a period of time; and/or it can be taken some period of time priorto consuming food.

As a result of the food effect discovery, various improved therapeuticmethods are provided, including: where short term exposure is desired,with a more rapid onset and shorter duration of effect, doxepinpreferably can be taken without food; in order to increase thebioavailability of the drug where rapid onset and shorter duration arenot issues, doxepin preferably can be taken with food; and to assuremore consistent efficacy, doxepin preferably can be taken in a fixedrelationship to food consumption, regardless of whether the drug istaken with our without food. Short term exposure with more rapid onsetcan be preferable when treating, for example, a sleep disorder, whileincreased bioavailability and/or consistent kinetics can be preferablefor treating conditions such as depression and anxiety.

Doxepin HCl is a tricyclic compound currently approved for treatment ofdepression and anxiety. The recommended daily dose for the treatment ofdepression or anxiety ranges from 75 milligrams to 300 milligrams. Also,U.S. Pat. Nos. 5,502,047 and 6,211,229, the entire contents of which areincorporated herein by reference, describe the use of doxepin for thetreatment chronic and non-chronic (e.g., transient/short term) insomniasat dosages below those used to treat depression. A food effectassociated with doxepin treatment of currently approved disorders orsleep disorders has not previously been reported.

Methods of Improving the Pharmacokinetics of Doxepin

Some embodiments relate to methods of improving the pharmacokinetics ofdoxepin, including by administering doxepin with or without food. Anumber of pharmacokinetic parameters can be affected by taking doxepinwith or without food, including for example, T_(max), C_(max), and thearea under the curve (AUC). Furthermore, various therapeutic regimenscan be utilized to take advantage of the doxepin food effects.

Affecting Maximum Concentration (T_(max)):

As discussed above, administration of doxepin without food or in afasted state can result in shortening the time required to achieve amaximum plasma concentration (T_(max)) of doxepin. Achieving a shorterT_(max) can be desirable since onset of drug action can be more rapidand the duration of drug action may be shortened. Some embodimentsrelate to methods of shortening the time required to achieve a maximumplasma concentration or a T_(max) of doxepin in a patient receivingdoxepin therapy, which methods can include administering to the patienta therapeutically effective amount of doxepin in a pharmaceuticalcomposition without food.

Also, it should be noted that other embodiments relate to methods ofincreasing the time required to achieve a maximum concentration ofdoxepin in a patient by administering doxepin with food.

Some embodiments relate to methods of preventing a doxepin food effectin order to minimize the time required for onset of action of the drug.The methods can include administering doxepin to a patient in needthereof, wherein the patient is in a fasted state or has not eaten orwill not eat within a particular time period. The methods further caninclude providing instructions to take the doxepin without food or in afasted state.

Use of Doxepin in Sleep Related Indications:

Knowledge of the food effect disclosed herein is useful in determiningan optimum regimen for providing doxepin sleep therapy. In patientsreceiving sleep therapy, the onset of action is an importantconsideration. The studies disclosed herein demonstrate that takingdoxepin with food can significantly increase T_(max). As a result, sleeppatients who take doxepin without food would be expected to have fastersleep onset or faster drug action in comparison to those who takedoxepin with food.

Thus, some embodiments relate to improved methods of treating a sleepdisorder. The methods can include providing a patient with atherapeutically effective amount of doxepin and providing the patientwith instructions to take the doxepin without food. In some aspects,doxepin can be administered without food in order to minimize the amountof time to achieve sleep onset or to otherwise minimize the amount oftime before drug action occurs.

The information regarding the doxepin food effect can be provided to thepatient. The information can include, for example, instructions that maybe provided to patients receiving doxepin therapy or health careprofessionals involved in treatment of those patients that the doxepinshould be administered without food, preferably separated from food forthe time periods discussed above. By way of example, such instructionscould be provided orally or in written form. Some exemplary writtenforms include a label associated with the drug, on the container for thedrug, packaged with the drug, or separately given to the patient apartfrom the drug, including providing the patient with access to a websiteor other electronic information with the instructions/information.

Affecting Overall Concentration (C_(max)) or Bioavailability:

The maximum plasma concentration or overall bioavailability of doxepincan be affected by food or a lack thereof. Increasing concentration orbioavailability can be desirable in some circumstances. Some embodimentsrelate to methods of increasing the oral bioavailability of doxepin to apatient receiving doxepin therapy. The methods can include administeringto the patient a pharmaceutical oral dosage form of doxepin with food.The administration can result in a greater AUC than if the drug is takenwithout food. The methods can include administering to the patient atherapeutically effective amount of doxepin in a pharmaceuticalcomposition with food or within a relatively short time of consumingfood (e.g., 15 minutes, 30 minutes, one hour, etc.).

Also, some embodiments relate to a method of increasing the maximumplasma concentration of doxepin in a patient receiving doxepin therapycomprising administering to the patient a therapeutically effectiveamount of doxepin in a pharmaceutical composition with food.

It should be noted that other embodiments relate to methods ofdecreasing the oral bioavailability or AUC of doxepin by administeringdoxepin without food.

Use of Doxepin in Depression and Anxiety

Doxepin has been used for several decades in the treatment of depressionand anxiety. Several side effects have been reported in connection withthe use of doxepin to treat depression or anxiety. The studies disclosedherein show that by taking doxepin with food, AUC was increased by 41%compared to taking doxepin in a fasted state. Because AUC(bioavailability) is increased by taking doxepin with food, a patientcan take a lower dose compared to when a patient takes doxepin withoutfood. Increasing the oral bioavailability or AUC of doxepin, anddecreasing dosage required for treatment can minimize or alleviate sideeffects and improve the safety and tolerability of doxepin therapy.Thus, in some aspects it can be preferred that patients receivingdoxepin for depression or anxiety should take the drug with food, or inclose proximity to eating. Some embodiments relate to improved methodsof treating depression and anxiety. The methods can include providing apatient with a therapeutically effective amount of doxepin and providingthe patient with instructions to take the doxepin with food. Asdiscussed more fully herein, administering doxepin with food can resultin an increase in the bioavailability of doxepin. As a result a patientcan take less doxepin, which can be safer and more tolerable for thepatient.

In some aspects, information, including instructions may be provided topatients receiving doxepin therapy or health care professionals involvedin treatment of those patients regarding a doxepin food effect and/orthat the doxepin should be administered with food, or at least inrelatively close proximity to eating food or eating a meal (for example,within one hour or less). By way of example, such information orinstructions could be provided orally or in written form. Some exemplarywritten forms include a label associated with the drug, on the containerfor the drug, packaged with the drug, or separately given to the patientapart from the drug, including providing the patient with access to awebsite or other electronic information with theinstructions/information. The invention further includes a package ofdoxepin with such written instructions associated therewith.

It should be noted that some aspects of the invention also relate tomethods of treating depression or anxiety by administering doxepinwithout food. Such embodiments can also include instructions to take themedication without food.

Improved Pharmacokinetic Consistency and Efficacy:

Still further embodiments relate to methods for improving theconsistency of pharmacokinetics associated with doxepin therapy, inwhich a patient receives a multiple doxepin dosages over multiple days.The methods can include administering the doxepin to the patient in afixed temporal relationship to food intake by the patient. Also, themethod can further include providing instructions to the patient to takethe doxepin in a fixed temporal relationship to food intake by thepatient. As discussed more fully herein, taking doxepin in fixed orconsistent temporal relationship to food can lead to improved safety andtolerability for the patient, for example, due to less variability inthe drug kinetics in the patient.

Kits and Products:

Furthermore, some embodiments relate to kits and products for a therapythat includes the use of doxepin. The kits and products can includedoxepin and instructions to take the doxepin without food or in a fastedstate, or to take the doxepin with food or within a predetermined periodof eating food.

The instructions or information regarding a food effect can be providedorally or verbally, or could be in written form. Some exemplary writtenforms include a label associated with the drug, on the container for thedrug, packaged with the drug, or separately given to the patient apartfrom the drug, including providing the patient with access to a web siteor other electronic information with the instructions/information. Theinvention further includes a package of doxepin with such writteninstructions associated therewith or with information on where to accessthe instructions/information (e.g., a website).

Administration of Doxepin

In performing the methods, doxepin, a pharmaceutically acceptable saltof doxepin, or prodrug of doxepin can be administered in any suitableoral form. Also, doxepin, or a pharmaceutically acceptable salt or aprodrug thereof can be administered to a patient. (It should beunderstood that the term “administer” and its variants are intended tocover both self-administration and administration by another person orby a device).

Doxepin can be administered without food or in a fasted state. Forexample, doxepin can be administered at least about 30 minutes to about4, 5, 6 or more hours after consuming food. More preferably, doxepin canbe taken at least about 1 hour to about 6 hours after consuming food. Insome aspects doxepin can be taken at least about 1, 2, 3, 4, 5 6 or morehours after consuming food.

Also, doxepin can be administered at least about 30 minutes to about 6hours before consuming any food, or more preferably, at least about 1hour to about 3 hours before consuming food. In some aspects, doxepincan be administered about 1, 2, 3 or more hours before food is consumed.

In some embodiments of the invention, such as when doxepin is used tofacilitate sleep, instructions may be provided to patients receivingdoxepin therapy or health care professionals involved in treatment ofthose patients that the doxepin should be administered without food,preferably separated from food for the time periods discussed above.Also, the patient can be provided with information regarding a doxepinfood effect. In other embodiments of the invention, such as when doxepinis used to treat depression or anxiety, instructions may be provided topatients receiving doxepin therapy or health care professionals involvedin treatment of those patients that the doxepin should be administeredwith food, or at least in relatively close proximity to eating food oreating a meal (for example, within one hour or less).

Again, by way of example, such instructions or information regarding afood effect could be provided orally or verbally, or could be in writtenform. Some exemplary written forms include a label associated with thedrug, on the container for the drug, packaged with the drug, orseparately given to the patient apart from the drug, including providingthe patient with access to a website or other electronic informationwith the instructions/information. The invention further includes apackage of doxepin with such written instructions associated therewith.

It should be recognized that in some cases, the food effect disclosedherein can appropriately play a part in designing customized dosingregimens that reflect the preferences of a particular healthcareprofessional or their patient. Thus, for example, in doxepin therapy(e.g., chronic doxepin therapy), such as therapy for depression oranxiety, it is customary to titrate the dosage; in other words,typically start with a lower dose and then increase it to the minimumdose that is sufficiently effective for the patient in question. In thistype of situation, there may be instances when doxepin is administeredwithout food, even though more drug will be required to achieve the sameeffect. In such cases, consistency is important to maintainingequivalent pharmacological effects. In other words, if a patient onchronic doxepin therapy is receiving a titrated dose that has beendetermined when the patient is consistently taking doxepin with food, orconsistently taking doxepin without food, then food-induced variationsin doxepin pharmacokinetics should not be a factor in therapeuticresponse or side effects. Thus, for chronic doxepin therapy, oneembodiment includes administering doxepin in a consistent relationshipto food intake, regardless of whether it is or is not taken with food.

Suitable routes of administration of doxepin can include any route inwhich significant quantities of drug reach the stomach, including oral,buccal, and sublingual administration.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Administration though oralpathways can be accomplished, for example, using a capsule, a tablet, agranule, a spray, a syrup, a liquid, powder, granules, pastes (e.g., forapplication to the tongue). Oral administration can be accomplishedusing fast-melt formulations, for example. For example, rapidly-meltingstrips or sheets that include the drug and suitable excipients can beprepared that dissolve quickly in the mouth, using well-knownformulation technology. For buccal or sublingual administration, thecompositions may take any suitable form, for example, tablets orlozenges. Pharmaceutical preparations for oral use can be obtained bymixing one or more solid excipient with pharmaceutical combination ofthe invention, optionally grinding the resulting mixture, and processingthe mixture of granules, after adding suitable auxiliaries, if desired,to obtain tablets or dragee cores.

Pharmaceutical preparations which can be used orally include forexample, liquid solutions, powders, and suspensions in bulk or unitdosage forms. Also, the oral formulations can include, for example,pills, tablets, granules, sprays, syrups, pastes, powders, boluses,pre-measured ampules or syringes, push-fit capsules made of gelatin, aswell as soft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. The push-fit capsules can contain the activeingredients in admixture with filler such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds may bedissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin, or liquid polyethylene glycols. In addition, stabilizers maybe added. All formulations for oral administration should be in dosagessuitable for such administration.

A variety of techniques for formulation and administration can be foundin Remington: The Science and Practice of Pharmacy (20^(th) ed.,Lippincott Williams & Wilkens Publishers (2003)), which is incorporatedherein by reference in its entirety.

Compositions

As mentioned above, doxepin, pharmaceutically acceptable salts, and/orprodrugs of the same can be used alone or in combination with othersubstances, such as for example, other insomnia or sleep medications, orwith other medications that treat a primary illness. Doxepin alone or incombination with other drugs can be included as part of a composition.The compounds and compositions can include any suitable form of thecompound for pharmaceutical delivery, as discussed in further detailherein.

The compositions and formulations disclosed herein also can include oneor more pharmaceutically acceptable carrier materials or excipients.Such compositions can be prepared for storage and for subsequentadministration. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical art, and are described, for example, inthe incorporated material of Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)),which is incorporated herein by reference in its entirety. The term“carrier” material or “excipient” herein can mean any substance, notitself a therapeutic agent, used as a carrier and/or diluent and/oradjuvant, or vehicle for delivery of a therapeutic agent to a subject oradded to a pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral administration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improve appearance of the composition.Acceptable excipients include sugars (such as lactose, sucrose,mannitol, sorbitol), starch powder, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, orderivatives thereof, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinyl-pyrrolidone (PVP), and/or polyvinyl alcohol,saline, dextrose, lecithin, albumin, sodium glutamate, cysteinehydrochloride, and the like. Examples of suitable excipients for softgelatin capsules include vegetable oils, waxes, fats, semisolid andliquid polyols. Suitable excipients for the preparation of solutions andsyrups include, without limitation, water, polyols, sucrose, invertsugar and glucose. Suitable excipients for injectable solutions include,without limitation, water, alcohols, polyols, glycerol, and vegetableoils. If desired, the compositions can include disintegrating agents maybe added, such as the cross-linked polyvinyl pyrrolidone, agar, oralginic acid or a salt thereof such as sodium alginate. Thepharmaceutical compositions can additionally include preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorings, buffers, coating agents, or antioxidants.Compositions for oral administration can be formulated according toconventional pharmaceutical practice as described in the incorporatedmaterial in Remington: The Science and Practice of Pharmacy (20^(th) ed,Lippincott Williams & Wilkens Publishers (2003)). For example,dissolution or suspension of the active compound in a vehicle such aswater or naturally occurring vegetable oil like sesame, peanut, orcottonseed oil or a synthetic fatty vehicle like ethyl oleate or thelike may be desired. Buffers, preservatives, antioxidants and the likecan be incorporated according to accepted pharmaceutical practice. Thecompound can also be made in microencapsulated form.

One can also administer the compounds of the invention in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin the incorporated materials in Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)).

Dosage

The selected dosage level can depend upon, for example, the conditionbeing treated, the route of administration, the severity of thecondition being treated, and the condition and prior medical history ofthe patient being treated. However, it is within the skill of the art tostart doses of the compound at levels lower than required to achieve thedesired therapeutic effect and to gradually increase the dosage untilthe desired effect is achieved. It will be understood, however, that thespecific dose level for any particular patient can depend upon a varietyof factors including the genetic makeup, body weight, general health,diet, time and route of administration, combination with other drugs andthe particular condition being treated, and its severity. For thetreatment of insomnia, preferably one dose is administered prior tobedtime.

As mentioned above, in some embodiments the preferable dosage can bebetween about 0.001 milligrams and about 350 milligrams. In someaspects, the dosage can be about 50 milligrams to about 350 milligrams.More preferably, the dosage can be between about 75 milligrams and 300milligrams. Also, in some aspects, the dosage can be between about 0.1milligrams and 20 milligrams or between about 0.5 milligrams and 10milligrams. The dosage also can be between about 1 milligram and about 6milligrams. Preferably, the dosage can be about 0.5 milligrams, 1milligram, about 2 milligrams, about 3 milligrams, about 4 milligrams,about 5 milligrams or about 6 milligrams. Further, the dosage can beabout 7 milligrams, about 8 milligrams, about 9 milligrams, or about 10milligrams. The lower dosage ranges are particularly desirable forsleep-related indications, while the higher dosage ranges areparticularly desirable for depression and anxiety-related indications.

EXAMPLES Example 1 Assessment of the Effect of Food on thePharmacokinetics of Doxepin

A study assessed the effect of food on the pharmacokinetics (PK) ofdoxepin in healthy subjects. It was a single-center, phase 1,randomized, open-label, single dose, two-way crossover study conductedin sixteen healthy, young adult male and female subjects. Screeningprocedures were performed within 14 days prior to enrollment.

Following screening procedures and baseline assessments, eligiblesubjects were randomly assigned to one of two treatment sequences(fed-fasted or fasted-fed). Subjects received a single 6 milligram doseof doxepin in the morning under either fed or fasted conditions on 2dosing days (Day 1 and Day 8). There were approximately 7 days betweeneach dose. Enrolled subjects were admitted to the study center on theevening before study drug dosing (Day 0 and Day 7) and remained at thestudy center for approximately 5 days. All subjects were dosed underboth fed and fasted conditions during the study as illustrated in FIG.1.

Subjects being dosed under fasted conditions were required to fastovernight for at least 10 hours prior to study drug administration andfor 4 hours after study drug administration. Fluids were restricted from1 hour predose to 1 hour postdose, except for water taken at the time ofdosing. Subjects being dosed under fed conditions were dosedapproximately 5 minutes after eating a high-fat, high-caloriestandardized breakfast (to be ingested within 25 minutes). Subjects wererequired to ingest the entire contents of the breakfast. All subjectswere required to remain in bed for approximately 4 hours after dosing.

Contents of the high-fat, high-calorie standardized breakfast were:

Two eggs fried in butter;

Two slices of bacon;

240 mL (8 fl. oz) whole milk;

57 g (2 oz) of hash browned potatoes; and

Two slices of toasted white bread with butter.

The total amount of protein, fat, and carbohydrate that made up thismeal was approximately 33, 55, and 58 g, respectively. The total caloriecontent was approximately 850 kcal.

Subjects were dosed on Day 1 and Day 8. The PK profiles were evaluatedon Days 1 through 5 and Days 8 through 12. Blood samples were collectedat predose (0 hour) and at 0.08, 0.17, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4,6, 8, 12, 24, 36, 48, 60, 72, and 96 hours postdose. The samples wereanalyzed for doxepin and doxepin metabolite concentrations in plasma.Plasma concentrations of doxepin were measured using validated highperformance liquid chromatography coupled to tandem mass spectrometry.The lower limit of quantification for doxepin was 0.05 ng/mL. Thefollowing PK parameters were estimated by noncompartmental methods usingactual elapsed time from dosing:

-   C_(max) (ng/mL) Maximum observed plasma concentration, obtained    directly from the observed concentration versus time data.-   T_(max) (h) Time to maximum plasma concentration, obtained directly    from the observed concentration versus time data.-   AUC_(0-∞) (ng·h/mL) Area under the curve from time zero extrapolated    to infinity, calculated by linear up/log down trapezoidal summation    and extrapolated to infinity by addition of the last quantifiable    concentration divided by the elimination rate constant    (AUC_(0-Tlast)+C_(last)/λ_(z)). If the extrapolated area    (C_(last)/λ_(z)) was greater than 30% of AUC_(0-∞), then AUC_(0-∞)    was set to missing.-   AUC_(0-Tlast) (ng·h/mL) Area under the curve from time zero to time    of last measurable concentration, calculated by linear up/log down    trapezoidal summation.-   AUC₀₋₂₄ (ng·h/mL) Area under the curve from time zero until 24    hours, calculated by linear up/log down trapezoidal summation. If    the 24 h sample was missing or below the lower limit of    quantification, AUC_(0-Tlast) was to be reported as AUC₀₋₂₄.-   AUC₀₋₄₈ (ng·h/mL) Area under the curve from time zero until 48    hours, calculated by linear up/log down trapezoidal summation. If    the 48 h sample was missing or below the lower limit of    quantification, AUC_(0-Tlast) was to be reported as AUC₀₋₄₈.-   AUC₀₋₇₂ (ng·h/mL) Area under the curve from time zero until 72    hours, calculated by linear up/log down trapezoidal summation. If    the 72 h sample was missing or below the lower limit of    quantification, AUC_(0-Tlast) was to be reported as AUC₀₋₇₂.-   AUC₀₋₉₆ (ng·h/mL) Area under the curve from time zero until 96    hours, calculated by linear up/log down trapezoidal summation. If    the 96 h sample was missing or below the lower limit of    quantification, AUC_(0-Tlast) was to be reported as AUC₀₋₉₆.-   λ_(z) (1/h) Elimination rate constant associated with the terminal    (log-linear) portion of the curve. This was estimated via linear    regression of time versus log concentration. Visual assessment was    used to identify the terminal linear phase of the concentration-time    profile. A minimum of three data points were used for determination.-   t_(1/2) (h) Apparent terminal half-life, determined as ln 2/λ_(z).-   CL/F (L/h) Apparent oral clearance, calculated as dose divided by    AUC_(0-∞).-   Vd/F (L) Apparent volume of distribution, calculated as    (CL/F)/λ_(z).

Concentration-Time Profiles

With reference to Table 1, following a single 6 milligram doseadministration of doxepin in fasted state (Treatment A) and fed state(Treatment B), mean plasma concentrations of doxepin increased, reachingC_(max) at 3.0 and 6.0 hours postdose, respectively. Doxepin plasmaconcentrations, reached mean C_(max) values of 0.854 and 0.951 ng/mL infasted and fed states, respectively. For both treatments, plasma doxepinconcentrations declined thereafter and remained quantifiable up to 48hours postdose (the lower limit of quantification was 0.05 ng/mL).Detectable plasma levels of doxepin were first observed at 30 minutespostdose in both the fed and fasted states (six and five subjects,respectively). All subjects had detectable concentrations of doxepin by90 minutes postdose. Median T_(max) was delayed by approximately 3.0hours in the fed state (6.0 hours) as compared to the fasted state (3.0hours). However, the range of values was similar for both treatments.Mean t_(1/2) values were comparable for fed and fasted states (16.5versus 14.4 hours, respectively).

TABLE 1 Summary Statistics [arithmetic mean (CV %)] of Plasma DoxepinPharmacokinetic Parameters Treatment [a] Parameter (unit) Fed (N = 16)Fasted (N = 15) C_(max) (ng/mL)  0.951 (58.8)  0.854 (63.2) T_(max) (h)[b]   6.0 (2.0-6.0)   3.0 (1.5-6.0) AUC_(0-∞)(ng · h/mL)   18.6 (70.2)  14.1 (80.6) AUC_(0-Tlast) (ng · h/mL)   16.8 (74.0)   12.6 (85.7)t_(1/2) (h)   16.5 (23.8)   14.4 (42.2) λ_(z) (1/h) 0.0445 (26.6) 0.0623(65.9) [a] 6 milligram doxepin tablet, under fed or fasted conditions.[b] Indicates median (range) values.

Table 2 shows the estimates of clearance and volume of distribution fordoxepin. Mean CL/F and Vd/F were 43% and 14% lower in the fed statecompared to the fasted state, respectively. Mean CL/F values were lowerin the fed (477 L/h) versus the fasted (837 L/h) states. Mean Vd/Fremained almost unchanged for fed (10280 L) and fasted (11930 L) states.

TABLE 2 Summary Statistics [arithmetic mean (CV%)] of Mean Clearance andVolume of Distribution for Doxepin Treatment [a] Parameter (unit) Fed (N= 16) Fasted (N = 15) CL/F (L/h)   477 (63.4)   837 (114.3) Vd/F (L)10280 (43.3) 11930 (46.9) [a] 6 milligram doxepin tablet, under fed orfasted conditions.

The effect of a high-fat meal on the pharmacokinetics of the 6 milligramdoxepin tablet was assessed and statistical comparisons of doxepinpharmacokinetic parameters between treatments are presented in Table 3.

The 90% confidence intervals for the ratio of population geometricleast-square means between fed and fasted treatments was not completelycontained within the equivalence limits of 80-125% for C_(max), and wereoutside the equivalence limits for AUC_(0-∞) and AUC_(0-Tlast),indicating that there was a food effect on exposure. Under fedconditions, AUC_(0-∞), AUC_(0-Tlast), and C_(max) were higher by 41%,46%, and 15%, respectively, compared to fasted conditions.

TABLE 3 Statistical Comparison of Doxepin Pharmacokinetic ParametersBetween Treatments Treatment Geometric Pairwise Comparisons Parameter(unit) [a] N LS Mean Pair Ratio (%) 90% CI AUC_(0-∞) (ng · h/mL) Fed 1615.14 Fed/Fasted 141.3 (124.7, 160.1) Fasted 15 10.72 AUC_(0-Tlast) (ng· h/mL) Fed 16 13.39 Fed/Fasted 145.6 (127.0, 166.9) Fasted 15 9.194C_(max) (ng/mL) Fed 16 0.822 Fed/Fasted 114.6 (101.8, 129.1) Fasted 150.717 Note: Results are based on mixed effect analysis of variance withsequence, period and treatment as fixed effects and subject withinsequence as a random effect. [a] 6 milligram doxepin tablet, under fedor fasted conditions.

CONCLUSIONS

Following a single 6 milligram dose of doxepin, a food effect wasobserved on the pharmacokinetics of doxepin. In the fed state, themaximum concentration (C_(max)) and exposure (AUC_(0-∞)) of doxepin wereapproximately 15% and 41% higher, respectively, compared to the fastedstate, and median T_(max) was delayed by approximately 3.0 hours. Theincrease in exposure was statistically significant and represents anincrease in bioavailability in the fed state (Table 4).

TABLE 4 Arithmetic Mean Arithmetic Mean Effect of Food Parameter (Fedcondition) (Fasted condition) (% of fasted state)^(a) AUC_(0-∞) 18.614.1 141 (ng · h/mL) C_(max) (ng/mL) 0.951 0.854 115 T_(max) (h)^(b) 6 3200 ^(a)Note that percentages documenting food effect on C_(max) and AUCare calculated from geometric LS means rather than the arithmetic meanspresented in this table ^(b)T_(max) is presented as a median value

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

We claim:
 1. A method of treating a sleep disorder, comprising:selecting a patient with insomnia; providing between about 0.5 mg and 7mg doxepin to the patient; and administering the doxepin to the patientwithout food.
 2. The method of claim 1, wherein the administeringwithout food comprises administering the doxepin at least about 30minutes after consuming food.
 3. The method of claim 1, whereinadministering without food comprises administering the doxepin at about1 hour prior to consuming food.
 4. The method of claim 1, wherein thedoxepin is provided in an amount of about 3 milligrams.
 5. The method ofclaim 1 wherein the doxepin is provided in an amount of about 6milligrams.
 6. The method of claim 1 wherein the doxepin is provided asa tablet, capsule or liquid.
 7. The method of claim 1, wherein thedoxepin is provided as a unit dosage form.
 8. The method of claim 1,wherein the doxepin is provided as an oral dosage form.
 9. In a methodof treating insomnia with doxepin, wherein an insomnia patient receivesa dosage of between 0.5 and 7 mg of doxepin, the improvement alteringthe pharmacokinetics of doxepin by providing the patient withinstructions to take the doxepin without food, and administering thedoxepin without food, thereby decreasing the time to reach maximumplasma concentration (T_(max)) in the patient, reducing C_(max), andreducing the area under the curve (AUC compared to administering thedoxepin with food.
 10. The method of claim 9, wherein decreasing thetime to reach maximum plasma concentration (T_(max)) in the patient,reducing C_(max), and/or reducing the area under the curve (AUC)shortens the time required to achieve sleep onset and/or reducesnext-day sedation effects.
 11. The method of claim 9, wherein theinstructions indicate a dosage of 6 milligrams.
 12. The method of claim9, wherein the doxepin is provided as a tablet, capsule or liquid. 13.The method of claim 9, wherein the doxepin is provided as a unit dosageform.
 14. The method of claim 9, wherein the doxepin is provided as anoral dosage form.
 15. A method of treating a sleep disorder with doxepinwhile achieving a desired alteration in doxepin pharmacokinetics,comprising: identifying a patient with insomnia; providing between 0.5mg and 7 mg doxepin to the patient; instructing the patient to take thedoxepin without food; and administering the doxepin to the patientwithout food, thereby decreasing the time to reach a maximum plasmaconcentration (T_(max)) in the patient, reducing C_(max), and reducingthe area under the curve (AUC), compared to administering the doxepinwith food.
 16. The method of claim 15, decreasing the time to reachmaximum plasma concentration (T_(max)) in the patient, reducing C_(max),and/or reducing the area under the curve (AUC) shortens the timerequired to achieve sleep onset and/or reduces next-day sedationeffects.
 17. The method of claim 15, wherein the therapeuticallyeffective amount is about 6 milligrams.
 18. The method of claim 15,wherein the doxepin is provided as a tablet, capsule or liquid.
 19. Themethod of claim 15, wherein the doxepin is provided as a unit dosageform.
 20. The method of claim 15, wherein the doxepin is provided as anoral dosage form.